Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCATU66)

• DOT Name: Galactose-1-phosphate uridylyltransferase (GALT)
• Synonyms: Gal-1-P uridylyltransferase; EC 2.7.7.12; UDP-glucose--hexose-1-phosphate uridylyltransferase
• Gene Name: GALT
• Related Disease:
  Classic galactosemia
  Galactosemia
  Cataract
  Cerebellar ataxia
  Childhood apraxia of speech
  Galactose epimerase deficiency
  HIV infectious disease
  Intellectual disability
  Liver cirrhosis
  Metabolic disorder
  Trichohepatoenteric syndrome
  Galactokinase deficiency
  Inborn error of metabolism
  Neoplasm
• UniProt ID: GALT_HUMAN
• PDB ID: 5IN3; 6GQD
• EC Number: 2.7.7.12
• Pfam ID: PF02744 ; PF01087
• Sequence:
  MSRSGTDPQQRQQASEADAAAATFRANDHQHIRYNPLQDEWVLVSAHRMKRPWQGQVEPQ
  LLKTVPRHDPLNPLCPGAIRANGEVNPQYDSTFLFDNDFPALQPDAPSPGPSDHPLFQAK
  SARGVCKVMCFHPWSDVTLPLMSVPEIRAVVDAWASVTEELGAQYPWVQIFENKGAMMGC
  SNPHPHCQVWASSFLPDIAQREERSQQAYKSQHGEPLLMEYSRQELLRKERLVLTSEHWL
  VLVPFWATWPYQTLLLPRRHVRRLPELTPAERDDLASIMKKLLTKYDNLFETSFPYSMGW
  HGAPTGSEAGANWNHWQLHAHYYPPLLRSATVRKFMVGYEMLAQAQRDLTPEQAAERLRA
  LPEVHYHLGQKDRETATIA
• Function: Plays an important role in galactose metabolism.
• KEGG Pathway:
  Galactose metabolism (hsa00052)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of nucleotide sugars (hsa01250)
  Prolactin sig.ling pathway (hsa04917)
• Reactome Pathway:
  Galactose catabolism (R-HSA-70370)
  Defective GALT can cause GALCT (R-HSA-5609978)
• BioCyc Pathway: MetaCyc:HS06274-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic galactosemia	DISX7P8M	Definitive	Autosomal recessive	[1]
Galactosemia	DIS6V2Q3	Definitive	Autosomal recessive	[2]
Cataract	DISUD7SL	Strong	Biomarker	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[4]
Childhood apraxia of speech	DISIR974	Strong	Genetic Variation	[5]
Galactose epimerase deficiency	DIS16BDZ	Strong	Biomarker	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[8]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[9]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[10]
Galactokinase deficiency	DISEB0V4	moderate	Biomarker	[6]
Inborn error of metabolism	DISO5FAY	moderate	Altered Expression	[11]
Neoplasm	DISZKGEW	Limited	Biomarker	[12]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[18]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Galactose-1-phosphate uridylyltransferase (GALT).	[21]

References

• [1] Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase. Biochemistry. 1992 Jun 23;31(24):5430-3. doi: 10.1021/bi00139a002.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [4] Assessment of ataxia phenotype in a new mouse model of galactose-1 phosphate uridylyltransferase (GALT) deficiency.J Inherit Metab Dis. 2017 Jan;40(1):131-137. doi: 10.1007/s10545-016-9993-2. Epub 2016 Oct 25.
• [5] Outcomes analysis of verbal dyspraxia in classic galactosemia.Genet Med. 2000 Mar-Apr;2(2):142-8. doi: 10.1097/00125817-200003000-00005.
• [6] Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia.Dis Model Mech. 2013 Jan;6(1):84-94. doi: 10.1242/dmm.010207. Epub 2012 Jul 5.
• [7] Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-(4)(7) integrin antibody.Sci Adv. 2019 Jan 9;5(1):eaat7911. doi: 10.1126/sciadv.aat7911. eCollection 2019 Jan.
• [8] 'Durate variant with clinical signs' has alpha1 -antitrypsin genotype ZZ.J Med Genet. 1976 Feb;13(1):46-8. doi: 10.1136/jmg.13.1.46.
• [9] N- and O-linked glycosylation of total plasma glycoproteins in galactosemia.Mol Genet Metab. 2012 Aug;106(4):442-54. doi: 10.1016/j.ymgme.2012.05.025. Epub 2012 Jun 12.
• [10] Genetic linkage analysis of the carpal tunnel syndrome.Hum Hered. 1985;35(5):288-91. doi: 10.1159/000153564.
• [11] Mutational analysis of GALT gene in Greek patients with galactosaemia: identification of two novel mutations and clinical evaluation.Scand J Clin Lab Invest. 2017 Oct;77(6):423-427. doi: 10.1080/00365513.2017.1334262. Epub 2017 Jun 23.
• [12] Molecular approach to common causes of female infertility.Best Pract Res Clin Obstet Gynaecol. 2002 Oct;16(5):685-702. doi: 10.1053/beog.2002.0317.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [19] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.